On January 31 Amgen launches the first Humira biosimilar in the US, under an agreement struck with Abbvie back in 2017 that gave it a six-month head start on other copycats. The value of this lead to Amgen is hard to calculate – the terms of that deal were undisclosed, though royalty payments and possibly an up-front fee were involved. In any case, until 2024 there will be little incentive for switching, SVB analysts note, as formularies that included Humira biosimilars in 2023 did not give these products any advantages. Mid-2023 will see several others enter the market, and at this point differentiators could start to matter. Abbvie’s Humira is mostly sold as a high-dose concentration of active ingredient, and only Alvotech and Teva’s product, AVT02, can match this; that product’s FDA approval is still pending, however. Interchangeability is another important factor. Alvotech and Teva are gunning for this, as is Pfizer; Amgen and Organon are a bit behind here, though the former has indicated that it might achieve this later this year. By 2028 Humira biosimilars could be selling $2.8bn, according to Evaluate Pharma's consensus, with Amgen's Amjevita accounting for almost half of this number. 

Sales of Carvykti might have stalled, but Johnson & Johnson and Legend now have data that might expand the Car-T therapy’s reach in multiple myeloma. This is thanks to the Cartitude-4 study, which Legend today toplined as positive for its primary endpoint of progression-free survival. While Carvykti and Bristol Myers Squibb/2seventy Bio’s Abecma are both approved for fifth-line or later multiple myeloma, Cartitude-4 tested the earlier setting of second to fourth-line disease. Depending on the full numbers, Cartitude-4 could enable Carvykti to get ahead of Abecma, which last year scored in its own earlier-line trial, Karmma-3, a study that tested a slightly later setting, with patients additionally having to have failed Darzalex. Yet to be revealed is Cartitude-4’s absolute benefit, toxicities, how Carvykti did against each of the two choices of control, and whether the therapy helps patients live longer. Cowen analysts expect Cartitude-4 to have been 90% powered to show a 50% reduction in risk of progression at this interim analysis, and expect 11 months’ mPFS for control. Carvykti sold $55m in the fourth quarter, flat versus three months earlier and short of $60m+ consensus, as a shortage of lentivirus continued to bite.

One of the most notable aspects of the FDA's track record on complete response letters is that the agency seems to hand out a remarkably similar number each year. This much is true for the last five, with 2022 seeing 34 rebuffs, bang on the five-year average. There was a slight uptick in the peak pandemic year of 2020, when delays in manufacturing plant inspections presumably peaked, and this issue remained live last year. Those hit by the FDA's ongoing Covid travel restrictions included Alvotech and Teva with their Humira biosimilar, the China-based cancer players Junshi and Hutchmed, and UCB, whose US launch of an important new growth driver, the psoriasis drug bimekizumab, was painfully delayed. This factor should fade in 2023, and the numbers below do not point to any particular tightening up of reviews at the US regulator. The clampdown on accelerated approvals is more likely to crimp the volume of novel agents hitting the market in the future. Still, it is always important to remember the big caveat of this analysis, which is that it relies on company disclosure. Private developers and some larger groups might not always feel obliged to announce a knockback. 

Astrazeneca’s Imfinzi is the only anti-PD-(L)1 drug approved for biliary tract cancer, but it might not be alone for long. After this month’s Asco-GI conference saw Roche’s Tecentriq underwhelm here, today Merck & Co said Keytruda succeeded in the Keynote-966 study. The Merck trial is analogous to Astra’s registrational Topaz-1 study, combining Keytruda with chemo in first-line biliary tract cancer, and showing an effect on its primary endpoint, overall survival, that the company called “statistically significant and clinically meaningful”. The bar is low, as Imfinzi plus chemo added just over a month of median OS to chemo alone, cutting risk of death by 20%. Meanwhile, Roche’s approach, in the Imbrave-151 trial, was different, investigating Tecentriq with or without Avastin, and not having a chemo control arm. Adding Avastin to Tecentriq cut risk of progression by 24%, and risk of death by 26%, but neither effect hit statistical significance. Since this trial was uncontrolled the absolute benefit is of interest: six-month OS was 92% for the combo and 81% for Tecentriq alone, while in Topaz-1 it was around 75%. With hints of a benefit in a patient subset, biomarker studies are ongoing, Asco-GI heard.

Intuitive Surgical has two factors to blame for its 7% share price slide this morning, equivalent to a loss of around $6bn in market cap: a delay in the release of a next-gen surgical robot, and earnings that left analysts dissatisfied. Investors had been hoping for an announcement of a new system by the end of 2023, but on a call yesterday evening chief executive Gary Guthart said that though the group was investing in new generations of its multiport platform, no such product would launch this year. Mr Guthart said that increased data requirements in both Europe and the US had contributed to slower-than-expected development. Supply chain challenges will also have contributed. Whether the system might come in 2024 or even later is a question management declined to answer. Shareholders were also left mulling a fourth-quarter earnings per share figure of $1.23, beneath the $1.25-1.28 that analysts had pencilled in, though revenues held to expectations. With Medtronic now a player in this space – its Hugo robot got European approval for general surgical procedures in October – Intuitive needs to avoid these kinds of disappointments in future.

The late-stage failure last week of Johnson & Johnson’s HIV vaccine candidate exposes just how sparse the pipeline is for prophylactic approaches, despite years of trying. The latest stumble, in the Mosaico study in men who have sex with men, came after 2021’s disappointment in the Imbokodo study in young women in sub-Saharan Africa. A look at the development landscape shows only a handful of projects in early-stage trials. And one of these could be set to disappoint: Vir Biotechnology disclosed last year that there had been no sustained T-cell responses in the first two dosing cohorts of a phase 1 study of VIR-1111. Data from the third and highest-dose cohort are due this half, but the company seems to have shifted attention to a next-gen candidate, VIR-1388, slated to enter the clinic later in 2023. Moderna also has two shots on goal with its mRNA candidates, in studies set to complete this year. The pipeline is rounded out by Worcester HIV Vaccine, which has a second-generation polyvalent DNA/protein HIV vaccine (PDPHV) project in phase 1. Companies like Gilead are looking to therapeutic vaccines as potential HIV cures, but a prophylactic now looks even further away.

An earlier cut of the phase 2a Intergris-IPF trial contained an odd dose response that raised questions about bexotegrast (PLN-74809) in idiopathic pulmonary fibrosis. New higher-dose data have erased concerns for some: Pliant shares surged 54% in early trading, worth $500m in market cap. Forced vital capacity, a measure of lung function, significantly increased in patients treated with bexotegrast 320mg at 12 weeks, versus a decline in the placebo group. The magnitude of benefit beat expectations but the shape of the FVC curve prompted headscratching, with a surprisingly steep and early benefit fading away; on a call Pliant executives pointed to three "high responders" dropping out after four weeks. The developer also revealed activity, and a dose response, on biomarkers that it claims supports bexotegrast’s mechanism of action, described as inhibition of the integrins αvβ6 and αvβ1. No serious drug-related events emerged. Small patient numbers are a big caveat to interpreting these findings: only 21 patients were treated with 320mg, and 24-week readout, due in the second quarter, remains important. Pliant plans to start phase 2b around mid-year rather than pushing straight into phase 3 – this is prudent given that IPF has thwarted many apparently promising projects.

Zanidatamab looked good enough in Her2-amplified biliary tract cancers to persuade Jazz to part with $375m up front for the asset, but developing data in gastroesophageal adenocarcinoma must have helped seal the deal. The latest phase 2 update shows improvement on a prior cut presented at Esmo 2021, with the dual Her2 bispecific plus chemo generating an impressive 79% objective response rate. The data, which are still early, are tracking ahead of standard-of-care Herceptin plus chemo, and look at least as good as Keytruda/Herceptin/chemo in Keynote-811, a trial that won the triplet accelerated approval in 2021. This Keytruda combo generated results considered surprising, because the addition of PD-(L)1 blockade to Her2-targeting had not previously yielded much success. Could zanidatamab responses be improved by adding checkpoint inhibition? That question is being asked in the pivotal Herizon-GEA-01 trial, which reads out in 2024. Keytruda remains a threat, however, with full results from Keynote-811 expected any time. That result will provide the bar for Jazz and Zymeworks to beat, and given its burdensome diarrhoea side effect zanidatamab needs to impress to have a real chance to compete against the Merck machine.

A US complete response letter for Lilly’s Alzheimer’s hope donanemab was always possible, given that the project has yet to generate phase 3 data, though the apparent reason behind it comes as a surprise. Lilly has claimed that the CRL cites just one deficiency: its accelerated approval filing does not include enough patients with at least 12 months’ exposure to donanemab. Guidelines require the safety database to comprise at least 100 patients exposed for a minimum of one year. Crucially, Lilly stops dosing donanemab once patients’ plaque clears; though in the phase 2 Trailblazer-Alz trial 131 patients got donanemab, because of “the speed of plaque reduction many were able to stop dosing as early as 6 months”, Lilly says – a claim supported by donanemab’s mechanistic efficiency. The CRL throws attention forward to the phase 3 Trailblazer-Alz 2 study readout, which should come in the second quarter and could back full approval; most had always viewed this as donanemab’s real catalyst. Lilly must hope for sufficient patient exposures in the combined datasets, and will face another issue: Leqembi, whose confirmatory Clarity-AD study Eisai had filed the same day it got accelerated approval, might soon boast full approval of its own.

Given the mixed track record of Roche’s Tecentriq in perioperative cancer uses, today’s apparent success of the Imbrave-050 trial comes as a pleasant surprise. The study tested Tecentriq plus Avastin in adjuvant liver cancer, and the combo is said to have beaten active surveillance alone on its primary endpoint of relapse-free survival. The precise contribution of Avastin to this result is unknown, but the success comes after the same combo was approved three years ago for first-line inoperable liver cancer on the basis of Imbrave-150. Tecentriq’s other perioperative success was in adjuvant NSCLC, where the drug is approved in ≥1% PD-L1 expressers on the basis of Impower-010, and an Abraxane combo read out positively in the perioperative triple-negative breast cancer (TNBC) trial Impassion-031, albeit on pathological complete response, likely not an approvable endpoint. Apart from that Tecentriq monotherapy and combos have failed several pivotal perioperative trials, including Imvigor-010, Imagyn-050, Impassion-050 and Immotion-010; the next big readout, from Impassion-030 in adjuvant TNBC, is expected soon. Specifically in adjuvant liver cancer this year could also see data from three other anti-PD-(L)1 drugs: Shanghai Junshi’s toripalimab, Astrazeneca’s Imfinzi and Innovent’s sintilimab.